Integrated PhD Biomedical Science

阿尔茨海默病(AD)是大脑中的一种进行性疾病，错误折叠的蛋白质会积累，导致神经元及其连接的丧失。许多与阿尔茨海默病发病风险相关的基因与小胶质细胞功能有关。小胶质细胞是驻留在大脑中的免疫细胞，负责清除有害刺激。在阿尔茨海默病中，它们被激活持续一段时间，这可能会导致慢性神经炎，并导致疾病病理。在研究小胶质细胞基因时，SLC家族被认为对AD的发展具有非常高的预测价值。这一蛋白质家族被证明对协调免疫反应和系统调节炎症具有重要作用，这表明该基因可能通过调节小胶质细胞功能在大脑的免疫反应中发挥作用。在这个项目中，我们将利用已发表的数据库比较SLC家族的基因在非疾病和AD人类大脑中的表达，同时研究属于相同基因家族的具有相似功能的其他基因。我们还将使用人体组织来证实这些蛋白质在小胶质细胞中表达。随后，我们将使用可以分化为小胶质样细胞的人类细胞来创建一个模拟错误折叠蛋白质存在的细胞模型。然后，我们将诱导基因敲除，以研究我们感兴趣的基因在人类AD模型中的功能。因此，我们将对这些基因的表达和功能进行表征，以了解这些基因变异如何可能导致慢性神经炎和AD病理。

Alzheimer's disease (AD) is a progressive condition in the brain whereby there is accumulation of misfolded proteins, leading to the loss of neurons and their connections. Many genes associated with the risk of developing AD are implicated in microglial function. Microglia are immune cells which reside in the brain and are responsible for the clearance of harmful stimuli. In AD, they are activated for sustained periods which can lead to chronic neuroinflammation and contribute to disease pathology. When investigating microglial genes, the SLC family was identified as having a very high predictive value for AD development. This family of proteins has been shown to be important for coordinating immune responses and regulating inflammation systemically, suggesting that the gene may play a role in the immune response in the brain by regulating microglial function. In this project, we will compare the expression of genes from the SLC family in non-diseased and AD human brains using published databases, while investigating other genes belonging to the same gene family with similar functions. We will also use human tissue to confirm that these proteins are expressed in microglial cells. Subsequently, we will use human cells which can be differentiated into microglial-like cells to create a cellular model which mimics the presence of misfolded proteins. Then we will induce gene knockouts to study the function of our genes of interest in a human AD model. Hence, we will characterise expression and function of these genes to understand how the genetic variants may contribute to chronic neuroinflammation and AD pathology.